Method and apparatus for enhanced size reduction of particles using supercritical fluid liquefaction of materials

ABSTRACT

The present invention provides a method and an apparatus for forming particles using supercritical fluid. The method includes the steps of mixing a load material with a first flow of a supercritical fluid in a first mixing chamber having a primary mixing device disposed therein to form a melt, transferring the melt from the first mixing chamber to a second mixing chamber having a secondary mixing device disposed therein, mixing the melt with a second flow of the supercritical fluid in the second mixing chamber to form a lower viscosity melt, expanding the lower viscosity melt across a pressure drop into an expansion chamber that is at a pressure below the critical pressure of the supercritical fluid to convert the supercritical fluid to a gas and thereby precipitate the load material in the form of particles.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to an apparatus and a method for producingparticles using supercritical fluid and, more particularly, to anapparatus and a method for producing particles using a supercriticalfluid and a secondary mixing assembly.

2. Description of Related Art

Particles having very small diameters and a narrow range of particlesizes are desired for a variety of end-use applications such as, forexample in the production of pharmaceutical compositions. Severalprocesses have been developed over the years to produce single-componentand multi-component (i.e., composite) particles utilizing the enhancedmass-transfer properties and generally benign nature of supercriticalfluids, near-critical fluids and compressed gases. Unfortunately, it hasbeen very difficult to obtain small sized particles (diameters less than100 μm) with a narrow particle size distribution using such processes.

One such supercritical fluid processing technique is known in the art asParticles from Gas-Saturated Solutions (PGSS). In the conventional PGSStechnique, a compound or a mixture of compounds is plasticized with asupercritical fluid to form a plasticized mass or “melt” that is thenexpanded across a pressure drop. The rapid decrease in pressure causesthe supercritical fluid to change into a gas phase, which results insupersaturation and ultimately precipitation of the compound or mixtureof compounds as particles.

Particle agglomeration is frequently problematic in conventional PGSSprocessing. During particle formation, bridges can form between growingparticles, which can lead to large differences in particle size and wideparticle size distributions. Furthermore, particles produced byconventional PGSS processing techniques tend to exhibit a broad sizedistribution in sizes above 100 μm and tend to be non-uniform (i.e.,irregular) in shape.

Another problem typically associated with the conventional PGSS processis that mixtures of compounds tend to separate as they pass across thepressure drop. The separation phenomenon can make it difficult toproduce uniform composite particles, and can actually result in theproduction of an undesirable blend of particles that are formed of onematerial or the other, but not both materials. Homogeneous compositepolymer/drug micro-spheres and uniform coated particles are particularlydifficult to produce using the conventional PGSS process.

The particle agglomeration problem typically encountered with the PGSSprocess is exacerbated when the melt comprises one or more compoundsthat exhibit a relatively high melt viscosity. Polymers, which are oftenused as carriers or excipients for pharmaceutical compositions, tendexhibit a relatively high viscosity in such melts. Because of theundesirable viscosity and concentration of the polymer relative to thesupercritical fluid used to form the melt, efficient particle dispersionis difficult to obtain. Furthermore, the process is often plagued withnozzle clogging and poor particle coating efficiency. Demixing and poorwetting between the carrier and biologically active agents furtherreduces the coating efficiency and can lead to an undesirablenon-homogeneous particle coating.

BRIEF SUMMARY OF THE INVENTION

The present invention provides an apparatus and a method for producingparticles using supercritical fluid. The apparatus and method provideenhanced mixing between the supercritical fluid and a load material thatcomprises on or more compounds to be processed into particles. Theapparatus according to the invention comprises a first mixing chamberand a second mixing chamber that is in fluid communication with thefirst mixing chamber. A primary mixing device, which is preferably arotating mechanical agitator, is disposed in the first mixing chamberfor mixing the load material and a supercritical fluid, near-criticalfluid or compressed gas to form a melt. A secondary mixing device, whichis preferably a static mixing element, is disposed in the second mixingchamber for mixing the melt with a fresh supply of supercritical fluid,near-critical fluid or a compressed gas that enters the second mixingchamber through an inlet. The pressure in the first mixing chamber ispreferably higher than the pressure in the second mixing chamber, whichfacilitates material transfer from the first mixing chamber to thesecond mixing chamber. The apparatus according to the invention furthercomprises an expansion chamber that is in fluid communication with thesecond mixing chamber.

In accordance with the method of the invention, a melt is formed in afirst mixing chamber. The melt comprises a load material and asupercritical fluid, a near-critical fluid and/or a compressed gas. Inthe preferred embodiment of the invention, supercritical carbon dioxideis used. The melt passes from the first mixing chamber into the secondmixing chamber and is contacted with a stream of fresh supercriticalfluid, near-critical fluid or compressed gas, which mixes with andreduces the viscosity of the melt as it passes through the secondarymixing device. The lower viscosity melt exits the second mixing chamberand is expanded across a pressure drop into an expansion chamber.Expansion of the lower viscosity melt causes the supercritical fluid,near-critical fluid or compressed gas to flash or convert to a gasphase, causing supersaturation of the melt and precipitation of the loadmaterial in the form of particles. The particles will generally exhibita small size (mean diameters less than 100 μm) and a narrow particlesize distribution. If desired, the resultant particles can be milled orotherwise further processed. The apparatus and method of the inventionare particularly suitable for use in producing composite particles, forexample, polymer encapsulated drug particles.

In a second embodiment of the invention, one or more additionalcompounds are combined and mixed with the melt in the second mixingchamber. The additional compounds are preferably in liquid form, eitherneat or by virtue of having been dissolved or plasticized with a solventor supercritical fluid to facilitate mixing with the melt. It is thuspossible to mix biologically active compounds with lower viscositypolymer melts.

In all embodiments of the invention, the lower viscosity melt isdirected from the second mixing chamber into an expansion chamber,preferably by spraying through a nozzle having one or more fineapertures. The rapid decrease in pressure causes the supercriticalfluid, near-critical fluid and/or compressed gas to expand and flash orconvert to a gas phase. The decrease in concentration of thesupercritical fluid, near-critical fluid and/or compressed gas in themelt results in supersaturation and then precipitation of fineparticles. Adiabatic expansion also results in substantial cooling. As aresult, the melt solidifies in the form of fine particles, which aretypically porous. Diffusion of the supercritical fluid, near-criticalfluid and/or compressed gas from the melt due to temperature andpressure reduction further reduces particle size and may enhance theporosity of the particles.

The higher concentration of supercritical fluid and lower viscosity ofthe melt produced through the use of the secondary mixing device in thesecond mixing chamber advantageously facilitates the production ofparticles that a smaller size and a narrower particle size distributionthan can be achieved using conventional PGSS processing techniques.Simply increasing the amount of supercritical fluid in a mechanicallyagitated mixing chamber does not result in the advantages provided bythe present invention.

The foregoing and other features of the invention are hereinafter morefully described and particularly pointed out in the claims, thefollowing description setting forth in detail certain illustrativeembodiments of the invention, these being indicative, however, of but afew of the various ways in which the principles of the present inventionmay be employed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic drawing of an apparatus according to theinvention.

FIG. 2 is a scanning electron microscope (SEM) micrograph of particlesproduced in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

With reference to FIG. 1, an apparatus 100 according to the inventiongenerally comprises a first mixing assembly 110, a second mixingassembly 120 and an expansion assembly 130. The first mixing assembly110 comprises a first mixing vessel 140, an optional solvent pump (notshown), a supercritical fluid pump (not shown) that suppliessupercritical fluid into the mixing vessel 140 through an inlet 150, athermostat (not shown) and a first or primary mixing device.

The first or primary mixing device may consist of a static mixer or adynamic mixer or a combination of both. Static mixers are difficult touse in the first mixing chamber when the load material consists ofpowdered materials. In such a circumstance, a mechanical agitator mustbe used. Accordingly, the first or primary mixing device preferablycomprises a rotating mechanical agitator driven by a motor 160.

The first mixing vessel 140 is preferably tubular and has first andsecond ends that are spaced axially apart. The first mixing vessel 140has an inner surface that defines a mixing chamber 170. The pressure inthe mixing chamber 170 is maintained constant during operation. Thefirst mixing assembly 110 includes means for charging the mixing chamber170 with a load material.

A preferred lab-scale supercritical fluid pump is a P-200 high-pressurereciprocating pump commercially available from Thar Technologies, Inc.of Pittsburgh, Pa. Suitable alternative pumps include diaphragm pumpsand air-actuated pumps that provide a continuous flow of supercriticalfluid. The high-pressure pump preferably comes factory-equipped with aburst-type rupture disc, manufactured by Fike Inc. of Blue Springs, Mo.,which is plumbed into a pressure relief system. The supercritical fluidpump preferably supplies supercritical fluid through both a surge tankand a metering valve so as produce a pulse-free flow.

When the primary mixing device comprises a rotating mechanical agitatordriven by a motor 160, a shaft extends from the motor 160 through thesecond end of the first mixing vessel 110 into the first mixing chamber170. A rotor 180 is disposed at a distal end of the shaft and located inthe chamber 170. The mixing rate is controlled by the rotation speed andgeometry (type and diameter) of the rotor 180. The rotor 180 ispreferably a propeller-shaped two-bladed mixer. Other supplementalmechanical mixing elements such as baffles, rotors, turbines,shear-mixers can also be disposed within the first mixing chamber 170,if desired.

The second mixing assembly 120 includes interior walls that define asecond mixing chamber 190. A secondary mixing device is disposed withinthe second mixing chamber 190. The second mixing assembly 120 alsopreferably comprises a thermostat (not shown). The second mixing chamber190 is preferably cylindrical and has first and second ends that arespaced axially apart.

In the presently most preferred embodiment of the invention, thesecondary mixing device comprises a static mixer 200. Static mixershaving different geometries are well known in the art. It will beappreciated that the secondary mixing device can comprise a static mixeralone, a dynamic mixing device alone, or a combination of both. Examplesof suitable dynamic mixers are high-shear rotor-stator mixers, rotatingturbines and helicoidal (spiral) mixers.

The second mixing assembly 120 is in fluid communication with the firstmixing assembly 110. A release valve 210 is preferably disposed betweenthe first mixing assembly 120 and the second mixing assembly 120. Thepressure in the second mixing chamber 190 is maintained at a reducedpressure relative to the pressure in the first mixing chamber 170 tofacilitate flow of material from the first mixing chamber 170 to thesecond mixing chamber 190 through the release valve 210. The secondmixing chamber 190 is preferably in fluid communication with asupercritical fluid pump (not shown), which may be the same as ordifferent than the supercritical fluid pump in communication with thefirst mixing chamber 170. The supercritical fluid pump suppliedsupercritical fluid into the second mixing chamber 190 through an inlet220.

As noted, preferably one or more static mixing elements 200 are disposedwithin the second mixing chamber 190. Suitable static mixing elementsare commercially available from Koch Enterprise, Inc., which is nowowned by Sulzer Chemtech USA, Inc. of Pasadena, Tex. If desired, one ormore dynamic mixing elements such as high-shear, rotor-stator mixers,turbines and helicoidal (spiral) mixers, can also be disposed in thesecond mixing chamber and driven by a motor and a shaft. The secondarymixing device helps mix the melt transferred from the first mixingchamber 170 with the fresh supercritical fluid pumped into the secondmixing chamber 190, which forms a lower viscosity melt. The flow ofsupercritical fluid into the second mixing chamber 190 also assists theflow of the lower viscosity melt through the static mixing element 200.The static mixing element 200 preferably breaks the melt into relativelyfiner droplets, which can intimately and efficiently mix with the melt.

Backpressure regulators can be used to maintain the desired pressures inthe first and second mixing chambers during operation. A particularlysuitable backpressure regulator is a model 26-1700, which iscommercially available from Tescom, USA of Elk River, Minn.

A thermostat communicates with heating elements (not shown) that arepreferably located proximate to the first mixing assembly 110, thesecond mixing assembly 120, the expansion assembly 140 and the releasevalve 210. A controller communicates with and controls the optionalsolvent pump, the supercritical fluid pump or pumps, the thermostat, themotor 160 of the mixer apparatus, the backpressure regulators and therelease valves. Suitable controllers are interchangeable and arecommercially available.

The expansion assembly 140 comprises a vessel having an inner surfacethat defines an expansion chamber 230. The lower viscosity melt passesfrom the second mixing vessel 190 into the expansion chamber 230 througha nozzle 240 provided with one or more apertures having a very smalldiameter. The expansion chamber 230 is maintained at a substantiallylower pressure than the second mixing chamber 190, which is below thecritical pressure of the supercritical fluid. Thus, upon passing throughthe nozzle 240, the supercritical fluid flashes and changes phase tobecome a gas, which can be removed through a vent 250. The phase changeof the supercritical fluid to a gas results in the precipitation of theload material in the melt in the form of fine particles. One or morefilters can be used to trap or collect the precipitated particles.

In accordance with the method of the invention, the first mixing vessel170 is charged with a quantity of load material. The load material canbe a single compound or a mixture of two or more compounds such as abiologically active material and a coating agent. Alternatively, theload material can be or can include a biodegradable polymer, medicinalagent, pigment, toxin, insecticide, viral material, diagnostic aid,agricultural chemical, nutritional material, protein, alkyloid, peptide,animal and/or plant extract, dye, explosive, paint, polymer precursor,cosmetic, antigen, enzyme, catalyst, nucleic acid, zeolite, hormonegastrointestinal acid suppressant, surfactant, dispersing aid, andcombinations thereof. The load material can further include one or moreadditional materials such as, for example, a carrier, polymer, filler,disintegrant, binder, solubilizer, excipient, surfactant andcombinations thereof. A preferred load material is a combination of abiologically active material and a biodegradable polymer such as, forexample, a polysaccharide, polyester, polyether, polyanhydride,polyglycolide (PLGA), polylactic acid (PLA), polycaprolactone (PCL),polyethylene glycol (PEG) or a polypeptide.

An optional solvent that is a liquid below its critical temperature andpressure may also be introduced with the load material. Solvents can beused to further lower the viscosity of the melt during operation.Suitable solvents include, for example, water, alcohol, toluene, ethylacetate, methyl chloride, methylene chloride, dimethyl sulfoxide (DMSO),dimethyl formamide (DMF), other organic or inorganic solvents, andcombinations thereof. The solvent may have a solute dissolved therein.Thus, solvent is herein defined to include a solution of solvent andsolute. Solvent is also defined to include an emulsion or a dispersionof material suspended in the solvent.

Once the load material is charged to the first mixing chamber, thesupercritical fluid pump is activated to supply a quantity ofsupercritical fluid through a surge tank, a metering valve and into thefirst mixing chamber. The supercritical fluid contacts the load materialunder mixing conditions to form a melt 260. The addition of thesupercritical fluid by the supercritical fluid pump increases thepressure in the first mixing chamber. The controller maintains thepressure and temperature at predetermined levels. Preferably, thecontroller maintains the temperature and pressure such that thesupercritical fluid is maintained in a supercritical state.

The supercritical fluid is preferably supercritical carbon dioxide(“CO₂”). Suitable alternative supercritical fluids include water,nitrous oxide, dimethylether, straight chain or branched C1-C6-alkanes,alkenes, alcohols, and combinations thereof. Preferable alkanes andalcohols include ethane, ethanol, propane, propanol, butane, butanol,isopropane, isopropanol, and the like. The supercritical fluid is chosengenerally with reference to the ability of the supercritical fluid toplasticize the load material during a mixing and melt formationoperation. Although use of a supercritical fluid such as supercriticalcarbon dioxide is presently most preferred, there may be instances wherea near-critical fluid or a compressed or liquefied gas could be usedinstead of a supercritical fluid.

Once the supercritical fluid is introduced into the first mixing vessel,the motor of the mixer apparatus is engaged to rotate the shaft and therotor. If an optional solvent is desired, a solvent pump can be engagedto supply solvent into the first mixing chamber. The rotor mixes thesupercritical fluid, the optional solvent and the load material until asubstantially uniform melt 260 is achieved. The term “melt” means thatthe load material is solvated or sufficiently plasticized by thesupercritical fluid such that it behaves as a fluid or semi-fluid andthus can be processed accordingly.

If desired, in cases where the load material is charged into the firstmixing chamber as a solution, excess supercritical fluid can becirculated through the first mixing chamber to remove supercriticalfluid soluble solvents from the first mixing chamber. Alternatively, thesolvent can remain in the melt, or can be removed during subsequentprocess steps.

Once the melt 260 is sufficiently formed in the first mixing chamber,the backpressure regulator and the release valve are adjusted by thecontroller to transfer the melt from the first mixing chamber to thesecond mixing chamber. The pressure in the first mixing chamber can beadjusted such that it is greater in the first mixing chamber than in thesecond mixing chamber, which means that when the release valve isopened, the melt flows from the first mixing chamber to the secondmixing chamber. The pressure inside the second mixing chamber can beeffectively maintained at a constant predetermined pressure using abackpressure regulator.

A stream of fresh supercritical fluid such as supercritical carbondioxide is also introduced into the second mixing chamber using asupercritical fluid pump. The flow of the supercritical fluid, andoptionally gravity, pushes or drives the melt through the static mixersdisposed within the second mixing chamber. The fresh supercritical fluidblends and mixes with the melt forming a lower viscosity melt.

The expansion chamber, which is in fluid communication with the secondmixing chamber, is maintained at a temperature and pressure below thecritical point of the supercritical fluid. Most preferably, theexpansion chamber is maintained at or near ambient temperature andatmospheric pressure. The lower viscosity melt is expands across apressure drop through the nozzle into the expansion chamber. Thepressure reduction causes the supercritical fluid in the lower viscositymelt to flash to a gaseous phase. The loss of supercritical fluid fromthe melt increases the melt point and/or glass transition temperature ofthe load material in the melt, decreases the temperature of the loadmaterial in the melt, and expands to increase the volume of the loadmaterial in the melt. The melt rapidly solidifies into particles of loadmaterial 270, which can be collected using a filter 280 or othercollection means.

As noted hereinabove, the phase change of the supercritical fluid fromliquid to gas reduces the localized temperature of materials adjacent tothe expansion location (i.e., at the nozzle outlet), which is sometimescalled adiabatic expansion. If a nozzle heater is present, the nozzlecan be heated to reduce the level of solvent in the particles, and toaffect particle characteristics, such as size and morphology. If noheater is used, a temperature reduction that normally accompanies suchan expansion can further decrease particle size based on cryo-fracturingof the forming particles. Further, a portion of the supercritical fluidmay crystallize in response to the temperature reduction. Whether aportion of the supercritical fluid crystallizes is determined by factorssuch as the selection of supercritical fluid, and the temperature andpressure of the expansion chamber during operation.

If any materials were dissolved, and/or suspended in the supercriticalfluid, the dissolved or suspended materials precipitate or solidifyduring the expansion and phase change of the supercritical fluid. Inaddition, any other materials that were added to the melt during mixingand formation of the melt are also formed into the particles as acoating, core, microsphere, microcapsules, etc. The particles thus formcomposite particles that collect in the expansion chamber. Rather thandiscrete particles, the process parameters can be adjusted so that theexpanded material precipitates as a suspension, a foam, a web, or a gel,or the particles characteristics can be modified such that the particleshave different surface profiles or morphologies, for example sphere,rod, or other basic geometric shape, and can be discrete or can begrouped or agglomerated. The particles can also form a suspension in thesolvent if the solvent is not removed during the mixing or the expansionstep.

The following examples are intended only to illustrate the invention andshould not be construed as imposing limitations upon the claims. Thechemicals used in the following examples can be obtained from a varietyof chemical suppliers including, but not limited to, Alpha Aeser, Inc.of Ward Hill, Mass. and Spectrum Chemical Mfg. Corp. of Gardena, Calif.

EXAMPLE 1

5.17 g of polycaprolactone (PCL) and 0.06 g of trypsinogen were chargedto a first mixing chamber of an apparatus configured as shown in FIG. 1.The first mixing chamber had a volume of 100 ml and had a diameter of 32mm. The chamber was pressurized with carbon dioxide to a pressure of 30MPa and heated to a temperature of 321K. The carbon dioxide becamesupercritical. The contents of the first mixing chamber were mixedtogether using a mixing blade that rotated at a constant speed of 1280rpm. Mixing continued for 150 minutes. A PCL/trypsinogen melt was formedin the first mixing chamber.

The PCL/trypsinogen melt was flowed from the first mixing chamberthrough a valve and then through a nozzle into a second mixing chambercontaining a static mixing assembly. The nozzle had an aperture with adiameter of 760 μm. A 200 g/min flow of fresh carbon dioxide at 25-27MPa was flowed into the second mixing chamber through a carbon dioxideinlet. The PCL/trypsinogen melt mixed with the fresh carbon dioxide inthe static mixing assembly and thereby formed a lower viscosity meltmixture.

The lower viscosity melt mixture in the second mixing chamber wasexpanded across a pressure drop into an expansion chamber through a finenozzle having an aperture with a 250 μm diameter. At least a portion ofthe supercritical carbon dioxide changed phase to become a gas therebyresulting in supersaturation of the PCL/trypsinogen melt, whichprecipitated into PLC/trypsinogen composite particles. The carbondioxide gas was removed from the expansion chamber using a vent.Expansion of the lower viscosity melt mixture also resulted in atemperature reduction, which may have caused a portion of the carbondioxide to change phase and become solid particles. However, any solidcarbon dioxide particles that may have been collected in the expansionchamber with the PCL/trypsinogen composite particles would haveultimately been removed via sublimation. FIG. 2 shows a scanningelectron micrograph of the PCL/trypsinogen composite particles, whichhad a mean particle diameter of 17.4 μm.

EXAMPLE 2

10 g of PCL was charged to the first mixing chamber of the apparatus asused in Example 1. The first mixing chamber was pressurized with carbondioxide to a pressure of 30 MPa and heated to a temperature of 343K. Thecarbon dioxide became supercritical. The PCL and supercritical carbondioxide were mixed together using a mixing blade that rotated at aconstant speed of 1200 rpm. Mixing continued for 150 minutes. A PCL meltwas formed.

The PCL melt flowed from the first mixing chamber into the second mixingchamber containing the static mixing assembly. A 200 g/min flow of freshcarbon dioxide at 25-27 MPa was flowed into the second mixing chamberand mixed with the PCL melt to form a lower viscosity melt.

The lower viscosity melt flowed across a pressure drop from the secondmixing chamber into the expansion chamber through a fine silica nozzlehaving an aperture with 50 μm diameter. At least a portion of thesupercritical carbon dioxide changed phase and become a gas therebyresulting in supersaturation of the PCL melt, which precipitated intoPLC particles. The carbon dioxide gas was removed from the expansionchamber using a vent. Expansion of the lower viscosity melt alsoresulted in a temperature reduction, which may have caused a portion ofthe carbon dioxide to change phase and become solid particles. However,any solid carbon dioxide particles that may have been collected in theexpansion chamber with the PCL particles would have ultimately beenremoved via sublimation. The PCL particles collected in the expansionchamber had a mean particle diameter of 6.7 μm. Table 1 below listsdetailed particle size measurement data for the PCL particles formed inExample 2. TABLE 1 Size (μm) Frequency (%) Over (%) 22.80 0.00 0.0019.90 0.28 0.00 17.38 0.80 0.28 15.17 1.89 1.08 13.25 3.72 2.97 11.566.16 6.69 10.10 8.77 12.85 8.816 10.83 21.62 7.697 11.92 32.45 6.72011.84 44.37 5.867 10.77 56.21 5.122 9.40 66.98 4.472 7.76 76.38 3.9055.64 84.14 3.409 4.00 89.78 2.976 2.62 93.78 2.599 1.59 96.40 2.269 0.9297.99 1.981 0.48 98.91 1.729 0.25 99.39 1.510 0.12 99.64 1.318 0.0099.76 1.151 0.00 99.76 1.006 0.00 99.76 8.877 0.00 99.76 0.766 0.0099.76 0.669 0.00 99.76 0.584 0.00 99.76 0.510 0.00 99.76 0.445 0.0099.76 0.389 0.00 99.76 0.339 0.00 99.76 0.296 0.00 99.76 0.259 0.0099.76 0.226 0.00 99.76 0.197 0.12 99.76 0.172 0.12 99.88 0.150 0.00100.00

Additional advantages and modifications will readily occur to thoseskilled in the art. Therefore, the invention in its broader aspects isnot limited to the specific details and illustrative examples shown anddescribed herein. Accordingly, various modifications may be made withoutdeparting from the spirit or scope of the general inventive concept asdefined by the appended claims and their equivalents.

1. A method of forming particles, the method comprising: mixing a loadmaterial with a first flow of a supercritical fluid in a first mixingchamber having a primary mixing device disposed therein to form a melt;transferring the melt from the first mixing chamber to a second mixingchamber having a secondary mixing device disposed therein; mixing themelt with a second flow of the supercritical fluid in the second mixingchamber to form a lower viscosity melt; and expanding the lowerviscosity melt across a pressure drop into an expansion chamber that isat a pressure below the critical pressure of the supercritical fluid toconvert the supercritical fluid to a gas and thereby precipitate theload material in the form of particles.
 2. The method according to claim1 wherein the primary mixing device comprises a mechanical agitator. 3.The method according to claim 1 wherein the secondary mixing devicecomprises a static mixing assembly.
 4. The method according to claim 1wherein the supercritical fluid comprises supercritical carbon dioxide.5. The method according to claim 4 wherein the load material comprises abiologically active agent and a carrier.
 6. The method according toclaim 5 wherein the carrier is a biodegradable polymer.
 7. The methodaccording to claim 1 wherein the lower viscosity melt passes from thesecond mixing chamber into the expansion chamber through a nozzle havingone or more small apertures formed therein.
 8. The method according toclaim 1 wherein the load material is dissolved in a solvent prior beingmixed with the supercritical fluid in the first mixing chamber.
 9. Themethod according to claim 8 wherein the solvent is soluble in thesupercritical fluid and is extracted from the first mixing chamberbefore the melt is transferred to the second mixing chamber.
 10. Themethod according to claim 1 further comprising: contacting the melt witha solvent in the in the second mixing chamber; and recovering theparticles in the expansion chamber as a suspension in the solvent. 11.Particles formed in accordance with the method of claim
 1. 12. Anapparatus for producing particles, the apparatus comprising: a firstmixing chamber for receiving a load material and a first flow ofsupercritical fluid; a primary mixing device disposed in the firstmixing chamber for mixing the load material and the supercritical fluidtogether to form a melt; a second mixing chamber in fluid communicationwith the first mixing chamber for receiving the melt; an inlet in thesecond mixing chamber for receiving a second flow of supercriticalfluid; a secondary mixing device disposed in the second mixing chamberfor mixing the melt and the second flow of supercritical fluid to form alower viscosity melt; an expansion chamber in fluid communication withthe second mixing assembly, the expansion chamber having a vent forexpelling expanded supercritical fluid in the form of a gas from theexpansion chamber and a collector for collecting the load material inthe form of particles.